There is a wide variety of polymers which are foreign to the human body and which are used in direct contact with its organs, tissues and fluids. These polymers are known as polymeric biomaterials. There is a continuous search for new, improved polymers to provide enhanced materials which are biocompatible, have good bioabsorbtive/biodegrable properties, appropriate mechanical and physical properties and related structural characteristics which find use in the prescribed applications. Materials which provide superior characteristics as well as flexibility in formulation, manufacture and delivery of the material to a situs in the body are especially desirable.
The term “intelligent polymer” refers to a polymeric system able to develop a “dialog” with its environment, as a result of which it displays large and sharp chemical or physical changes, in response to small chemical or physical stimuli. These polymers are denominated smart, stimuli-responsive or environmentally sensitive polymers. Temperature, pH, ionic strength and electric field are among the most important stimuli, causing phase or shape changes which dramatically affects the optical, mechanical or transport properties of the compositions. A number of molecular mechanisms exist which can cause these sharp transitions and water plays a crucial role in most of them. These include: ionization, ion exchange, release or formation of hydrophobically bound water and helix-coil transition.
The desire to find improved polymeric compositions which can be used for specific medical and dental applications is ever present. A major problem which exists in utilizing known polymeric compositions in a diversity of applications, including medical and dental applications is the ability to deliver polymers to sites within the patient's body or mouth having sufficient viscosities to provide the appropriate physical/mechanical properties consistent with the task to be performed. This an acute problem especially where high viscosity is required because the delivery of the polymeric materials is generally very difficult and their conformability extremely limited.
One approach to solving this problem is that of Hubbell, et al. as described in U.S. Pat. No. 5,410,016. In this reference, the use of polymerizable water soluble macromers containing photopolymerizable end-cap groups such as acrylate groups, is described. In the method of Hubbell, in order to provide high viscosity polymeric materials at a site within a patient's body, Hubbell suggests delivering a lower viscosity mixture of the above-described macromers and then photopolymerizing the macromers in situ within the patient's body to obtain high viscosity gels. This approach suffers from the requirement of having to photopolymerize the macromers after they are placed in the body. Inasmuch as consistency, uniformability, (or homogeneity and reproducibility) of UV polymerization is often difficult to achieve even in a factory setting, the difficulties of providing consistent UV polymerization on a case-by-case basis is one major disadvantage of the system. In addition, providing conditions to facilitate photopolymerization in a patient's body is costly, requiring significant expenditures for photopolymerization equipment as well as high costs for calibrating and servicing the equipment. Moreover, using an intense UV energy source at the site of polymerization is difficult and often dangerous to the patient. The use of prepolymerized polymers represents a clear advantage over the Hubbell process.
One of the most important stimuli for influencing polymeric biomaterials is temperature. There are numerous biomedical applications where a sharp increase in viscosity within a narrow and clinically relevant temperature interval is a crucial feature. The phase transition temperature for these polymers is called the Lower Critical Solution Temperature (LCST). Since the transition is endothermic, the process is driven by the entropy gain, resulting from the release of water molecules bound to the hydrophobic groups in the polymer backbone. A feature common to the polymers exhibiting this behavior is the balance between hydrophilic and hydrophobic moieties in the molecules.
The development of temperature-responsive polymers has attracted much attention in recent years, due to their large clinical potential. The ability to inject, deliver or apply a low viscosity liquid which, upon contact with the tissue dramatically increases its viscosity is an extremely attractive characteristic. Recently, a number of polymeric system have been studied, with much of the work focusing on poly(ethylene oxide)/poly(propylene oxide)/poly(ethylene oxide) triblocks, because of their clinical potential. Despite their potential, these materials have failed to be used in the clinic because of inherent performance limitations. A critical inadequacy of these materials is that their viscosity at physiological temperatures is insufficient to provide adequate structure for useful biological activity. Insufficient viscosity affects the cohesiveness and mechanical properties of the material, which negatively impacts their physical stability and significantly reduces their residence time at the implantation site or site of activity. This fundamental limitation affects important properties, thus rendering these polymeric systems unsuitable. In addition, these materials release bioactive agents too quickly to be of clinical relevance.
One additional attrribute of many biomaterials is that the biodegradable/bioabsorbable. Early biodegradable/bioabsorbable polymers focused on polylactic and/or polyglycolic acid homopolymers or copolymers which were used primarily in bioabsorbable sutures. These early polymers suffered from the disadvantage that the polymers tended to be hard or stiff and often brittle with little flexibility. In addition, the kinetics of their degradation tended to be slow in certain applications, necessitating research on polymers with faster degradation profiles.
A number of other copolymers utilizing lactic acid, glycolic acid, ε-caprolactone, poly(orthoesters) and poly(orthocarbonates), poly(esteramides) and related polymers have been synthesized and utilized in medical applications with some measure of success. The polymers tend to be limited, however, by disadvantages which appear in one or more of the following characteristics: flexibility, strength, extensibility, hardness/softness, biocompatability, biodegradability, sterilizability, ease of formulation over a wide range of applications and tissue reactivity.
Recent investigative attention has centered on the production of polymeric compositions comprising polyester triblocks which are derived from blocks of poly(oxy)alkylene and polyhydroxycarboxylic acids. These formulations, among others, have exhibited favorable characteristics for use to reduce and/or prevent adhesion formulation secondary to surgery and other medical applications.
Despite the advances that the aforementioned polymeric compositions represent in the field of treating adhesions, with the advance of less invasive surgical techniques, work continues to find methods and compositions which are more easily delivered to sites in the body which have been surgically repaired using the newer surgical techniques. In particular, laparascopic surgical methods are now being used with increasing frequency. These methods produce favorable surgical results while significantly limiting the opening through which the surgery is performed. The limited openings result in increased difficulty to deliver anti-adhesion and related polymers, especially those of high viscosity or which are film-like, which may be advantageously used in a number of applications.